β-Cell-selective regulation of gene expression by nitric oxide. Am J Physiol Regul Integr Comp Physiol 2024 Jun 01;326(6):R552-R566
Date
04/08/2024Pubmed ID
38586887Pubmed Central ID
PMC11381020DOI
10.1152/ajpregu.00240.2023Scopus ID
2-s2.0-85195535629 (requires institutional sign-in at Scopus site) 2 CitationsAbstract
Nitric oxide is produced at low micromolar levels following the induction of inducible nitric oxide synthase (iNOS) and is responsible for mediating the inhibitory actions of cytokines on glucose-stimulated insulin secretion by islets of Langerhans. It is through the inhibition of mitochondrial oxidative metabolism, specifically aconitase and complex 4 of the electron transport chain, that nitric oxide inhibits insulin secretion. Nitric oxide also attenuates protein synthesis, induces DNA damage, activates DNA repair pathways, and stimulates stress responses (unfolded protein and heat shock) in β-cells. In this report, the time- and concentration-dependent effects of nitric oxide on the expression of six genes known to participate in the response of β-cells to this free radical were examined. The genes included Gadd45α (DNA repair), Puma (apoptosis), Hmox1 (antioxidant defense), Hsp70 (heat shock), Chop (UPR), and Ppargc1α (mitochondrial biogenesis). We show that nitric oxide stimulates β-cell gene expression in a narrow concentration range of ∼0.5-1 µM or levels corresponding to iNOS-derived nitric oxide. At concentrations greater than 1 µM, nitric oxide fails to stimulate gene expression in β-cells, and this is associated with the inhibition of mitochondrial oxidative metabolism. This narrow concentration range of responses is β-cell selective, as the actions of nitric oxide in non-β-cells (α-cells, mouse embryonic fibroblasts, and macrophages) are concentration dependent. Our findings suggest that β-cells respond to a narrow concentration range of nitric oxide that is consistent with the levels produced following iNOS induction, and that these concentration-dependent actions are selective for insulin-containing cells.
Author List
Naatz A, Yeo CT, Hogg N, Corbett JAAuthors
John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of WisconsinNeil Hogg PhD Associate Dean, Professor in the Biophysics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsApoptosis Regulatory Proteins
Cell Cycle Proteins
Gene Expression Regulation
HSP70 Heat-Shock Proteins
Heme Oxygenase (Decyclizing)
Heme Oxygenase-1
Insulin
Insulin-Secreting Cells
Membrane Proteins
Mice
Nitric Oxide
Nitric Oxide Synthase Type II
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Proto-Oncogene Proteins
Rats
Transcription Factor CHOP
Transcription Factors
